Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling. Targeting cancer stem cells in medulloblastoma by inhibiting AMBRA1 dual function in autophagy and STAT3 signalling

Medulloblastoma (MB) is a childhood malignant brain tumour comprising four main subgroups characterized by different genetic alterations and rate of mortality. Among MB subgroups, patients with enhanced levels of the c-MYC oncogene (MBGroup3) have the poorest prognosis. Here we identified a previously unrecognized role of the pro-autophagy factor AMBRA1 in regulating MB. We demonstrated that AMBRA1 expression levels strongly depend on c-MYC expression and correlate with patient poor prognosis; also, knockdown of AMBRA1 reduces MB stem potential, growth and migration of MBGroup3 cells in vitro and in vivo. At a molecular level, AMBRA1 mediates these effects by suppressing SOCS3, an inhibitor of STAT3 activation. In turn, active STAT3 increases c-MYC expression that, in a positive feedback loop, sustains AMBRA1 transcription. Importantly, pharmacological inhibition of autophagy profoundly affects stem potential and metastasization of MBGroup3 cells in vitro and in vivo, and a combined anti-autophagy and anti-STAT3 approach impacts MBGroup3 cell survival. Taken together, our data identified the c-MYC/AMBRA1/STAT3 axis as a strong oncogenic signalling pathway with significance for both patient stratification strategies and targeted treatments of MBGroup3. Overall design: Characterization of the global gene expression changes induced by AMBRA1 or by ATG7 siRNA-mediated downregulation